The Orthomyxoviruses have three types of influenza viruses, termed as A, B, and C, that are classified according to the antigenic differences between their nucleoprotein (NP) and matrix 1 (M1) proteins as demonstrated in the traditional serological assays. We identified a novel influenza virus from swine exhibiting influenza-like illness. Its overall amino acid sequence shares approximately 50 % identity with that of ICV. Phylogenetic analysis further found that it is most closely related to ICV, rather than to IAV and IBV. However, the distance between the new virus and ICV was similar to the differences between IAV and IBV for the most of genomic segments. Recently, we also found the prevalence of C/OK-like virus in cattle. The incidences of C/OK and C/OK-like viruses in both cattle and swine provides strong evidence of cross-species transmission, highlighting their potential threat to human health because of closely physical contacts between humans and these farm animals. Additionally, this group of viruses may undergo reassortment with currently circulating human ICV to generate new antigenic variants that could pose a threat to human and animal health. The potential impact on human health and the novel properties in biology and molecular genetics warrant further investigation into this group of new viruses, which form the foundation of this R21 proposal. Major goals of this R21 project are to develop reverse genetics systems (RGS) for these novel viruses, identify their receptor, elucidate a functional role of vira HE protein in cell tropism and temperature restriction of virus replication, define viral mutation rates, and importantly determine whether human ICV and these new viruses can undergo reassortment to produce viable viruses. Successful completion of this project will provide novel insights to evolution, biology, and genetics of this new group of emerging viruses that have a potential threat to human health.